Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein

Abstract

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL–DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.

Development of phenyllactic acid ionic liquids and evaluation of cytotoxicity to human cervical epithelial cells

“…39 Carnitine-based ILs have also been utilised to synthesise herbicidal ionic liquids with low toxicity and enhanced biodegradability, 40 and to stabilise and solubilise antimicrobial eye drops. 41 Hence, we envisaged that endogenous cations, choline and l -carnitine, could be readily used to transform d - and l -PLA into ILs. Our previous studies show that the biocompatible anion used for the synthesis of ILs impacts the solubility and in vitro cytocompatibility of ILs.…”

Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance

“…Diacerein (DIA, 71, Figure 23) is an unstable anthraquinone prodrug with poor water solubility, hydrolyzed into active rhein (72, Figure 23), and commonly used in the treatment of osteoarthritis. In 2023, Grassiri et al [53] proposed its repurposing as an antibacterial agent against ocular keratitis, often caused by P. aeruginosa and S. aureus bacterial strains. Hence, new eye-drops were formulated using betaine-and carnitine-based ionic liquids (IL) [Bet6-IL (73) and Carn6-IL (74), Figure 23] as excipients capable of self-assembling into nanoaggregates, promoting DIA's solubilization and stability while enhancing its ocular residence time.…”

Unlocking the Anticancer Potential of Ionic Liquids

“…Alendronic acid [44] IL1-IL4 Another study focused on the use of ILs to enhance the solubility and stability of diacerein (DIA), an anthraquinone prodrug with poor solubility and stability, commonly used for treating osteoarthritis and bacterial keratitis [60]. In this study, two natural zwitterionic compounds, L-carnitine and betaine, were modified by attaching an alkyl ester group and a bromide ion to the sixth carbon atom of the original molecules, resulting in the formation of bio-based ILs known as L-carnitine C6 alkyl ester bromide (Carn6) and betaine C6 alkyl ester bromide (Bet6).…”